Dong Xiaonan, Liang Qiren, Pan Yun-Zu, Wang Xiaoyu, Kuo Yi-Chun, Chiang Wei-Chung, Zhang Xuewu, Williams Noelle S, Rizo Josep, Levine Beth, De Brabander Jef K
University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
ACS Med Chem Lett. 2022 Aug 12;13(9):1510-1516. doi: 10.1021/acsmedchemlett.2c00309. eCollection 2022 Sep 8.
Autophagy plays essential roles in a wide variety of physiological processes, such as cellular homeostasis, metabolism, development, differentiation, and immunity. Selective pharmacological modulation of autophagy is considered a valuable potential therapeutic approach to treat diverse human diseases. However, development of such therapies has been greatly impeded by the lack of specific small molecule autophagy modulators. Here, we performed structure-activity relationship studies on a previously discovered weak Bcl-2 inhibitor SW076956, and developed a panel of small molecule compounds that selectively released Bcl-2-mediated inhibition of autophagy-related Beclin 1 compared to apoptosis-related Bax at nanomolar concentration. Our NMR analysis showed that compound directly binds Bcl-2 and specifically inhibits the interaction between the Bcl-2 and Beclin 1 BH3 domains without disruption of the Bcl-2-Bax BH3 interaction. More broadly, this proof-of-concept study demonstrates that targeting protein-protein interactions of the intrinsic autophagy regulatory network can serve as a valuable strategy for the development of autophagy-based therapeutics.
自噬在多种生理过程中发挥着重要作用，如细胞内稳态、新陈代谢、发育、分化和免疫。自噬的选择性药理学调节被认为是治疗多种人类疾病的一种有价值的潜在治疗方法。然而，由于缺乏特异性小分子自噬调节剂，此类疗法的开发受到了极大阻碍。在此，我们对先前发现的一种弱Bcl-2抑制剂SW076956进行了构效关系研究，并开发了一组小分子化合物，这些化合物在纳摩尔浓度下与凋亡相关的Bax相比，能选择性地解除Bcl-2介导的对自噬相关的Beclin 1的抑制作用。我们的核磁共振分析表明，该化合物直接结合Bcl-2，并特异性抑制Bcl-2与Beclin 1 BH3结构域之间的相互作用，而不会破坏Bcl-2-Bax BH3相互作用。更广泛地说，这项概念验证研究表明，针对内在自噬调节网络的蛋白质-蛋白质相互作用可作为开发基于自噬的治疗方法的一种有价值策略。
